The long-term objective of this research theme seeks to identify the most potent components of particulate matter (PM) and to develop strategies for reducing its health impacts. This project focuses on combustion- derived PM (cdPM), and its research is to link molecular pathways in lung cells that are associated with adverse cellular responses to cdPM and adverse human health effects with (a) specific and environmentally relevant cdPM physicochemical properties and (b) changes in these properties as a result of atmospheric transformationsandconditioning.Theinnovationisbasedontheabilityto(a)reliablysynthesizecdPMunder tightlycontrolledconditionstoobtainspecificproperties,(b)tomimickeyatmospherictransformations,and(c) collect cdPM in a manner that will preserve the properties of interest during exposure of target cells. This approachwillminimizeconfoundingfactorsandenhancethereproducibilityoftheresults,anditwillallowthe projecttoexplorehowthesedistinctphysicochemicalpropertieslinkto:cellularuptake;?toxicity;?inflammatory responses;?CYPenzymeregulation;?andactivationofTRPionchannels.Althoughthesearerelativelystandard measures, these measures are good indicators of in vivo models and human health effects. The Specific Aimsinclude:(1)thecompletionofacomprehensivecareerdevelopmentplanthatbuildsknowledgethrough hands-onexperienceandformaltraining;?(2)thesynthesisofcdPMgeneratedunderconditionsthatmimickey atmospheric transformations, resulting in real-world differences in shape, size, and composition;? and (3) the linkingofcdPMphysicochemicalpropertiestopathologicallyimportantoutcomesinprimaryandimmortalized lung cells with in vivo and human-health relevance. Much cdPM exposure is through particle inhalation and interactions with the lung. These research objectives complement the proposal?s comprehensive career development plan that promotes an independent research career for PI, Dr. Kelly. The proposed project focuses on cdPM because it is a significant contributor to atmospheric PM levels, and cdPM emission regulations focus on PM mass concentration. However, changes in cdPM physicochemical properties associatedwithnewfuelsandnewenginetechnologiestendtobeconsideredonlyafterthesechangeshave alreadybeenimplemented,leadingtounintendedconsequences.Thisapplicationoffersanopportunityfora researcher trained in combustion, cdPM generation/characterization to gain skills in biological sciences enabling a more comprehensive and systematic approach to understanding the effects of cdPM physical propertiesonhealthandbiologicaloutcomes.Completionoftheproposedprojectwillprovideconclusivenew findings about how cdPM size, shape, and composition modify biological processes that may be pivotal in linkingairpollutiontocommonlyobservedadverseoutcomesinrespiratorytissue.Thisinformationisessential for developing improved metrics that link the PM?s health effects to health outcomes and for developing exposuremitigationstrategiestailoredtothemostpotentcharacteristicsofPM.